The effort to investigate the gender differences in lupus has been mostly devoted to the cellular and humoral immune responses and much less to the cellular damage. Recently cell death, the ultimate cell damage, has been recognized as a fundamental pathogenic mechanism in lupus glomerulonephritis (GN). GN is among the most devastating effects of lupus disease. It is the leading cause of long-term disability, and ranks high as a cause of morbidity and mortality. Despite the striking 9:1 female to male lupus ratio, GN is more severe in males, suggesting that the molecular pathways in both sexes involved in the renal damage must be as aggressive. We have recently discovered that the inhibition or deletion of poly (ADP) ribose polymerase (PARP) 1, an enzyme involved in necrotic cell death and production of pro-inflammatory cytokines, protects only male mice from lupus GN, demonstrating the principle that males and females employ different pathways of cellular damage downstream the immune complex deposition, a fundamental initiator of renal damage. Therefore the objective of this application is to investigate the molecular pathways that induce tissue damage, necrotic cell death and inflammation in males and females during lupus GN. We propose that cell death during lupus GN is a fundamental renal intrinsic pathogenic mechanism that actively participates to the disease progression. We also propose that during GN there is a balance between the pro-inflammatory necrotic death and the anti-inflammatory apoptosis, and when this balance is toward necrosis the disease is more severe and progresses at a faster pace. In AIMs I and II we intend to demonstrate in mouse models of lupus GN that these pathways are regulated by two major factors: 1) PARP-1, which induces necrosis, increases the release of pro-inflammatory cytokines, such as high molecular group box (HMGB)-1, modulates the expression of adhesion molecules, and facilitates the activation of NF?B in situ~ and 2) estrogens, which modulate the expression of adhesion molecules, cytokines and the induction of apoptotic versus necrotic cell death via inactivation of PARP-1. Because there are two major pathways that lead to necrotic cell death, PARP-1-dependent and Receptor Interacting Protein (RIP)-1 and -3-dependent, and because necrosis also occurs in females, in AIM I and II we also intend to determine if females have proclivity for RIP-1/3-dependent necrosis. In the third AIM we will test the relevance of necrotic cell death pathways in human lupus nephritis. We will test the hypothesis that HMGB1 released during nephritis might be a biomarker in human lupus GN. The rationale for our project is that a better understanding of the pathways regulating the tissue damage in lupus GN pathophysiologies in males and females will lead to a tailored and better treatment for each gender.